Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

Ge Zhang, Bjarke Feenstra, Jonas Bacelis, Xueping Liu, Lisa M Muglia, Julius Juodakis, Daniel E Miller, Nadia Litterman, Pan-Pan Jiang, Laura Russell, David A Hinds, Youna Hu, Matthew T Weirauch, Xiaoting Chen, Arun R Chavan, Günter P Wagner, Mihaela Pavličev, Mauris C Nnamani, Jamie Maziarz, Minna K KarjalainenMika Rämet, Verena Sengpiel, Frank Geller, Heather A Boyd, Aarno Palotie, Allison Momany, Bruce Bedell, Kelli K Ryckman, Johanna M Huusko, Carmy R Forney, Leah C Kottyan, Mikko Hallman, Kari Teramo, Ellen A Nohr, George Davey Smith, Mads Melbye, Bo Jacobsson, Louis J Muglia

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BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 −8) or an association with suggestive significance (P<1.0×10 −6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.

OriginalsprogEngelsk
TidsskriftThe New England Journal of Medicine
Vol/bind377
Udgave nummer12
Sider (fra-til)1156-1167
ISSN0028-4793
DOI
StatusUdgivet - 21. sep. 2017

Fingeraftryk

Premature Birth
Mothers
Datasets

Citer dette

Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L. M., Juodakis, J., ... Muglia, L. J. (2017). Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. The New England Journal of Medicine, 377(12), 1156-1167. https://doi.org/10.1056/NEJMoa1612665
Zhang, Ge ; Feenstra, Bjarke ; Bacelis, Jonas ; Liu, Xueping ; Muglia, Lisa M ; Juodakis, Julius ; Miller, Daniel E ; Litterman, Nadia ; Jiang, Pan-Pan ; Russell, Laura ; Hinds, David A ; Hu, Youna ; Weirauch, Matthew T ; Chen, Xiaoting ; Chavan, Arun R ; Wagner, Günter P ; Pavličev, Mihaela ; Nnamani, Mauris C ; Maziarz, Jamie ; Karjalainen, Minna K ; Rämet, Mika ; Sengpiel, Verena ; Geller, Frank ; Boyd, Heather A ; Palotie, Aarno ; Momany, Allison ; Bedell, Bruce ; Ryckman, Kelli K ; Huusko, Johanna M ; Forney, Carmy R ; Kottyan, Leah C ; Hallman, Mikko ; Teramo, Kari ; Nohr, Ellen A ; Davey Smith, George ; Melbye, Mads ; Jacobsson, Bo ; Muglia, Louis J. / Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. I: The New England Journal of Medicine. 2017 ; Bind 377, Nr. 12. s. 1156-1167.
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abstract = "BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 −8) or an association with suggestive significance (P<1.0×10 −6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.",
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author = "Ge Zhang and Bjarke Feenstra and Jonas Bacelis and Xueping Liu and Muglia, {Lisa M} and Julius Juodakis and Miller, {Daniel E} and Nadia Litterman and Pan-Pan Jiang and Laura Russell and Hinds, {David A} and Youna Hu and Weirauch, {Matthew T} and Xiaoting Chen and Chavan, {Arun R} and Wagner, {G{\"u}nter P} and Mihaela Pavličev and Nnamani, {Mauris C} and Jamie Maziarz and Karjalainen, {Minna K} and Mika R{\"a}met and Verena Sengpiel and Frank Geller and Boyd, {Heather A} and Aarno Palotie and Allison Momany and Bruce Bedell and Ryckman, {Kelli K} and Huusko, {Johanna M} and Forney, {Carmy R} and Kottyan, {Leah C} and Mikko Hallman and Kari Teramo and Nohr, {Ellen A} and {Davey Smith}, George and Mads Melbye and Bo Jacobsson and Muglia, {Louis J}",
year = "2017",
month = "9",
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Zhang, G, Feenstra, B, Bacelis, J, Liu, X, Muglia, LM, Juodakis, J, Miller, DE, Litterman, N, Jiang, P-P, Russell, L, Hinds, DA, Hu, Y, Weirauch, MT, Chen, X, Chavan, AR, Wagner, GP, Pavličev, M, Nnamani, MC, Maziarz, J, Karjalainen, MK, Rämet, M, Sengpiel, V, Geller, F, Boyd, HA, Palotie, A, Momany, A, Bedell, B, Ryckman, KK, Huusko, JM, Forney, CR, Kottyan, LC, Hallman, M, Teramo, K, Nohr, EA, Davey Smith, G, Melbye, M, Jacobsson, B & Muglia, LJ 2017, 'Genetic Associations with Gestational Duration and Spontaneous Preterm Birth', The New England Journal of Medicine, bind 377, nr. 12, s. 1156-1167. https://doi.org/10.1056/NEJMoa1612665

Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. / Zhang, Ge; Feenstra, Bjarke; Bacelis, Jonas; Liu, Xueping; Muglia, Lisa M; Juodakis, Julius; Miller, Daniel E; Litterman, Nadia; Jiang, Pan-Pan; Russell, Laura; Hinds, David A; Hu, Youna; Weirauch, Matthew T; Chen, Xiaoting; Chavan, Arun R; Wagner, Günter P; Pavličev, Mihaela; Nnamani, Mauris C; Maziarz, Jamie; Karjalainen, Minna K; Rämet, Mika; Sengpiel, Verena; Geller, Frank; Boyd, Heather A; Palotie, Aarno; Momany, Allison; Bedell, Bruce; Ryckman, Kelli K; Huusko, Johanna M; Forney, Carmy R; Kottyan, Leah C; Hallman, Mikko; Teramo, Kari; Nohr, Ellen A; Davey Smith, George; Melbye, Mads; Jacobsson, Bo; Muglia, Louis J.

I: The New England Journal of Medicine, Bind 377, Nr. 12, 21.09.2017, s. 1156-1167.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

AU - Zhang, Ge

AU - Feenstra, Bjarke

AU - Bacelis, Jonas

AU - Liu, Xueping

AU - Muglia, Lisa M

AU - Juodakis, Julius

AU - Miller, Daniel E

AU - Litterman, Nadia

AU - Jiang, Pan-Pan

AU - Russell, Laura

AU - Hinds, David A

AU - Hu, Youna

AU - Weirauch, Matthew T

AU - Chen, Xiaoting

AU - Chavan, Arun R

AU - Wagner, Günter P

AU - Pavličev, Mihaela

AU - Nnamani, Mauris C

AU - Maziarz, Jamie

AU - Karjalainen, Minna K

AU - Rämet, Mika

AU - Sengpiel, Verena

AU - Geller, Frank

AU - Boyd, Heather A

AU - Palotie, Aarno

AU - Momany, Allison

AU - Bedell, Bruce

AU - Ryckman, Kelli K

AU - Huusko, Johanna M

AU - Forney, Carmy R

AU - Kottyan, Leah C

AU - Hallman, Mikko

AU - Teramo, Kari

AU - Nohr, Ellen A

AU - Davey Smith, George

AU - Melbye, Mads

AU - Jacobsson, Bo

AU - Muglia, Louis J

PY - 2017/9/21

Y1 - 2017/9/21

N2 - BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 −8) or an association with suggestive significance (P<1.0×10 −6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.

AB - BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 −8) or an association with suggestive significance (P<1.0×10 −6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.

KW - Adenylyl Cyclases/genetics

KW - Datasets as Topic

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Gestational Age

KW - Humans

KW - Peptide Elongation Factors/genetics

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Pregnancy

KW - Premature Birth/genetics

KW - Receptor, Angiotensin, Type 2/genetics

KW - Regression Analysis

KW - Trans-Activators/genetics

KW - Wnt4 Protein/genetics

KW - ras Proteins/genetics

U2 - 10.1056/NEJMoa1612665

DO - 10.1056/NEJMoa1612665

M3 - Journal article

C2 - 28877031

VL - 377

SP - 1156

EP - 1167

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

SN - 0028-4793

IS - 12

ER -

Zhang G, Feenstra B, Bacelis J, Liu X, Muglia LM, Juodakis J et al. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. The New England Journal of Medicine. 2017 sep 21;377(12):1156-1167. https://doi.org/10.1056/NEJMoa1612665